ARASENS: A phase 3 trial of darolutamide in males with metastatic hormone-sensitive prostate cancer (mHSPC)

Abstract

Background: While androgen-deprivation therapy (ADT) demonstrates antitumor activity in mHSPC with prolonged disease control, resistance ultimately occurs and patients die of castration-resistant PC (CRPC). Approximately 10-50% of PC subjects develop CRPC in<5 yr. Chemohormonal therapy per ESMO guidelines is recommended as first-line treatment of metastatic, castration-naïve disease in men fit enough for chemotherapy. Darolutamide (ODM-201) is a unique investigational oral androgen receptor (AR) antagonist that binds the AR and AR mutants (eg, W742L and F877L) with high affinity and selectivity, thus, inhibiting receptor function and dihydrotestosterone binding with negligible blood-brain barrier penetration. In the phase 1/2 ARADES and ARAFOR trials, darolutamide had antitumor activity and was well tolerated in men with mCRPC (Fizazi et al. Lancet Oncol 2014; Massard et al. Eur Urol 2016). As a result of this encouraging activity in mCRPC, the ARASENS trial is evaluating darolutamide plus standard ADT + docetaxel in men withmHSPC. Trial design: This international, randomized, double-blind, placebo-controlled, phase 3 trial (NCT02799602) is being conducted in 23 countries. 1300 men with newly diagnosed mHSPC will be randomized 1:1 to either 600 mg (2×300 mg) darolutamide BID with food, equivalent to a total daily dose of 1200 mg or placebo, both with ADT + docetaxel (6 cycles after randomization), and stratified by extent of disease and alkaline phosphatase levels. Key inclusion criteria are confirmed PC with documented metastases, started ADT6first-generation androgen inhibition therapy ≤12 wk before randomization, and Eastern Cooperative Oncology Group performance status 0 or 1. The primary objective is to show superior overall survival with darolutamide vs placebo, both with ADT + docetaxel. Secondary end points include time to CRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event-free survival (SSE-FS), time to first SSE, initiation of opioid use, pain progression, and worsening of physical symptoms, all measured at 12-wk intervals. Safety will be assessed. The trial is open for enrollment, FPFV was in November 2016, and>110 sites in 16 countries are enrolling.